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Definitions

• the present invention relates to substituted spiro compounds, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
• a suitable starting point for the treatment of pain, in particular of neuropathic pain is the vanilloid receptor of subtype 1 (VR1 / TRPV1), which is often referred to as the capsaicin receptor.
• This receptor is u.a. by vanilloids such as e.g. Capsaicin, heat and protons stimulates and plays a central role in the onset of pain.
• vanilloids such as e.g. Capsaicin, heat and protons stimulates and plays a central role in the onset of pain.
• it is important for a variety of other physiological and pathophysiological processes such as migraine; Depressions; neurodegenerative diseases; cognitive disorders; Anxiety; Epilepsy; To cough; diarrhea; pruritus; Disorders of the cardiovascular system; Disorders of food intake; Drug addiction; Drug abuse and especially urinary incontinence.
• n 0, 1 or 2
• R 1 is a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted, optionally at least one heteroatom chain member having aliphatic radical;
• an unsubstituted or at least monosubstituted aryl or heteroaryl radical which is attached via a linear or branched, unsubstituted or at least monosubstituted, optionally at least one heteroatom as chain member having alkylene, alkenylene or alkynylene group and / or with a may be condensed unsubstituted or at least monosubstituted mono- or polycyclic ring system;
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently of one another, respectively
• R 2 , R 4 , R 5 , R 6 , R 7 and R 8 independently of one another, respectively
• a hydrogen radical or are a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted, optionally having at least one heteroatom as a chain member aliphatic radical;
• R 1 , R 2 , R 7 and R 8 are each a hydrogen radical
• R 9 is a hydrogen radical
• an unsubstituted or at least monosubstituted naphthyl or heteroaryl radical which may be condensed with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, for an unsubstituted or at least monosubstituted aryl or heteroaryl radical which is bonded via a - (CH 2 ) -, - (CH 2 ) 2- or - (CH 2 ) 3 group and optionally with an unsubstituted or at least monosubstituted or monocyclic ring system may be condensed;
• a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical an unsubstituted or at least monosubstituted, unsaturated or saturated, optionally at least one heteroatom as a ring member having cycloaliphatic radical having a linear or branched, unsubstituted or at least monosubstituted, optionally at least one heteroatom as a chain member alkylene, alkenylene or Alkynylene group bound and / or may be condensed with an unsubstituted or at least monosubstituted mono- or polycyclic ring system;
• Nitrogen atom as ring member form an unsubstituted or at least monosubstituted, unsaturated or saturated, optionally at least one further heteroatom as ring member having heterocycloaliphatic radical which may be condensed with an unsubstituted or at least monosubstituted mono- or polycyclic ring system;
• the substituents of the aforementioned aliphatic radicals can be independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2, -OH, -SH and -NH 2 ;
• the radicals R 10 , R 11 , R 12 , R 13 and R 14 preferably have alkylene, alkenylene or alkynylene groups, each independently selected from the group consisting of F, Cl, Br, -OH, -SH, -NH 2 , -CN, -NO 2 and phenyl may be substituted; where the phenyl radical having 1, 2, 3, 4 or 5 substituents independently of one another is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl Pentyl, isopentyl and neopentyl may be substituted.
• the radical R 10 in each of the definitions given herein may be an unsubstituted or at least monosubstituted phenyl radical, provided that not one of the meta positions and the para position of this phenyl radical is substituted with substituents each are bonded via an identical atom selected from the group consisting of oxygen, sulfur and nitrogen.
• substituents mentioned in the publication WO 2005/21515 A1 in the corresponding position are excluded.
• the radical R 10 may preferably comprise a phenyl radical as defined above or an unsubstituted or at least monosubstituted phenyl radical which is condensed with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, or an unsubstituted or at least simple substituted naphthyl or heteroaryl radical, which may be condensed with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, which is selected from the group consisting of naphthyl, (1,3) -benzodioxolyl, (1, 4) Benzodioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, thiazoly
• Aliphatic radicals in the context of this invention comprise acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or monosubstituted or polysubstituted by identical or different substituents, preferably having 1 to 20 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), more preferably 1 to 12 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12), very particularly preferably 1 to 6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, ie C1.20, C1-12, Ci-6-alkyls, C2-20-. C2-12, C2-6 alkenyls and C2-20-, C2-12-.
• alkenyls have at least one CC double bond and alkynyls at least one CC triple bond.
• aliphatic radicals can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 2-hexyl , n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-o
• the aliphatic radicals mentioned above can preferably have 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, -N (H) that is to say - and -N, having (Ci-C6 alkyl.).
• Preferred substituted aliphatic radicals are -CH 2 -CI, -CH 2 -Br, -CH 2 -CH 2 -CI, -CH 2 -CH 2 -Br, -CH 2 -CH 2 -CH 2 -Br and -CH 2 -CH 2 -CH 2 -CI.
• Cycloaliphatic radicals in the context of this invention are cyclic saturated or unsaturated hydrocarbon radicals having preferably 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, particularly preferably 3, 4, 5, 6, 7 or 8 carbon atoms, each radical being unsubstituted or monosubstituted or polysubstituted by identical or different substituents. Cycloaliphatic radicals preferably have 1, 2, 3, 4 or 5 heteroatoms independently selected from the group consisting of oxygen, nitrogen (NH) and sulfur.
• cycloaliphatic radical which may be bridged with 1 or 2 linear or branched C- ⁇ -5-alkylene groups and may be condensed with a mono- or polycyclic ring system, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, Cyclodecyl, cycloundecyl, cyclododecyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, [6,6] -dimethyl- [3.1.1] -bicycloheptyl, adamantyl, oxiranyl, aziridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothioazolidinyl, pyrazolidinyl
• a monocyclic or polycyclic ring system is understood to mean monocyclic or polycyclic hydrocarbon radicals which may be saturated or unsaturated and may optionally have 1, 2, 3, 4 or 5 heteroatom (s) as ring member (s) which are independently selected from the group consisting of oxygen, nitrogen and sulfur.
• a mono- or polycyclic ring system may, for example, be condensed (fused) with an aryl radical or a heteroaryl radical.
• a polycyclic ring system such as a bicyclic ring system
• the different rings may have a different degree of saturation, i. be saturated or unsaturated.
• a polycyclic ring system is a bicyclic ring system.
• aryl radicals which are condensed with a monocyclic or polycyclic ring system are [1,3] -benzodioxolyl, [1,4] -benzodioxanyl, [1,2,3,4] -tetrahydronaphthyl, [1, 2,3,4] -tetrahydroquinolinyl, [1, 2,3,4] -tetrahydroisoquinolinyl, [1, 2,3,4] -tetrahydroquinazolinyl, 2H-benzo [1,4] oxazine-3 (4H) -onyl, (3 , 4) - dihydroquinolin-2 (1H) -onyl and [3,4] -dihydro-2H-1,4-benzoxazinyl.
• aryl radical is preferably to be understood as meaning a radical which is selected from the group comprising phenyl, naphthyl, phenanthrenyl and anthracenyl and is unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
• Aryl is particularly preferably an unsubstituted or monosubstituted or polysubstituted, d. H. 2-, 3-, or 5-fold, identically or differently substituted phenyl, 1-naphthyl or 2-naphthyl.
• Heteroaryl radicals in the context of the present invention are heterocycles which are heteroaromatic.
• Heteroaryl radicals are preferably 5- to 14-membered, d. H. 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered and preferably have 1, 2, 3, 4 or 5 heteroatoms independently selected from the group comprising Oxygen, nitrogen and sulfur.
• Each heteroaryl radical can be unsubstituted or monosubstituted or polysubstituted, i. H. two, three, four or five times, the same or different substituted.
• heteroaryl radical in the context of the present invention are thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl , Pyrimidinyl, indazolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzo [2,1,3] thiadiazolyl, [1,2,3] benzothiadiazolyl, [2,1,3] - Benzoxadiazolyl and [1,2,3
• substituted is understood to mean the single or multiple, for example two, three, four or five times, substitution of one or more hydrogen atoms of the ring system by suitable substituents.
• R 10 is a substituted phenyl moiety, it can be particularly preferably selected from the group consisting of biphenyl, 2-pentafluoro-sulfanyl-phenyl, 2-methanesulfonamide-phenyl, 2-ethanesulfonamide-phenyl, 2-trifluoromethyl-phenyl, 2-butoxy-phenyl, 2- (1,1) -dimethyl-propylphenyl, 2-nitrophenyl, 2-ethylbenzoate, 2-acetamidophenyl, 2-dimethylamino-phenyl, 2-diethylamino-phenyl, 2-amino-phenyl, 2-benzene-sulfonamide, 2-trifluoromethyl- sulfanyl-phenyl, 2-ethyl-phenyl, 2-tert-butyl-phenyl, 2-methyl-benzoate, 2-methanesulfonyl-phenyl, 2-ethyl-a
• the linear or branched alkylene, alkenylene or alkynylene groups mentioned above preferably have 1 to to 5 carbon atoms, that is C- ⁇ - 5 alkylene, alkenylene or C 2 5 C 2 - 5 alkynylene groups each unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -SH, -NH 2 , -CN, -NO 2 and phenyl in which the phenyl radical having 1, 2, 3, 4 or 5 substituents independently of one another is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl may be substituted.
• alkylene, alkenylene or alkynylene groups have optionally in each case 1 or 2 heteroatom (s) selected from the group consisting of oxygen, nitrogen, that -N (H) -. And -N (C 1 6 alkyl ) -, and sulfur as a chain link (er) on.
• alkylene groups can be selected from the group consisting of - (CH 2 ) -, - (CH 2 ) 2 -, -C (H) (CH 3 ) -, -C (CH 3 J 2 -, - (CH 2 ) 3 -, - (CH 2 J 4 -, - (CH 2 ) 5 -, -C (H) (CH 3 ) - (CH 2 ) -, -C (H) (C 2 Hs) - (CH 2 ) -, -C (phenyl) 2 -, -C (H) (phenyl) -, - (CH 2 ) -O-, - (CH 2 JN (CH 3 ) -, - (CHz) -S-, - (CH 2 HCHs) -N (CH 3 ) - and - (CH 2 ) - (CH 2 ) - (CH 2 ) -N (C 2 H 5 ) -.
• An alkynylene group may preferably be -C ⁇ C-.
• n 0, 1 or 2
• R 1 is a linear or branched, saturated or unsaturated, optionally substituted C ⁇ M O aliphatic radical
• A-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic radical containing a saturated, unsaturated or aromatic, optionally substituted mono- or polycyclic ring system can be condensed;
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently of one another, respectively
• CM O aliphatic radical or are a linear or branched, saturated or unsaturated, optionally substituted CM O aliphatic radical
• R 2 , R 4 , R 5 , R 6 , R 7 and R 8 independently of one another, respectively
• CM O aliphatic radical or are a linear or branched, saturated or unsaturated, optionally substituted CM O aliphatic radical
• R 1 , R 2 , R 7 and R 8 are each a hydrogen radical
• R 9 is a hydrogen radical
• an optionally substituted 5- to 14-membered aryl or heteroaryl radical which may be condensed with a saturated or unsaturated, optionally substituted mono- or polycyclic ring system;
• R 10 is a linear or branched, saturated or unsaturated, optionally substituted CM O aliphatic radical
• 5- alkyl, -NH-Ci -5 -alkyl, -N (Ci- 5 -alkyl) 2 , -NH-C ( O) -OC 1 .
• an optionally substituted radical selected from the group consisting of naphthyl, (1,3) -benzodioxolyl, (1,4) -benzodioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [ b] furanyl, benzo [b] thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, benzisoxazolyl, [1, 2,3,4] -tetrahydronaphthyl,
• an optionally substituted 5- to 14-membered aryl or heteroaryl radical which may be condensed with a saturated or unsaturated, optionally substituted mono- or polycyclic ring system and / or via a - (CH 2 ) -, - ( CH 2 ) 2- or - (CH 2 ) 3 group;
• Ci.i O aliphatic radical for a linear or branched, saturated or unsaturated, optionally substituted Ci.i O aliphatic radical
• an optionally substituted 5- to 14-membered aryl or heteroaryl radical which may be condensed with a saturated or unsaturated, optionally substituted mono- or polycyclic ring system and / or bonded via a - (CH 2 ) group, stand;
• R 11 and R 12 or R 13 and R 14 together with the nitrogen atom connecting them form a saturated or unsaturated, optionally substituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic radical as ring member, which may be condensed with a saturated, unsaturated or aromatic, optionally substituted mono- or polycyclic ring system,
• Ci-io aliphatic radical or are a linear or branched, saturated or unsaturated, optionally substituted Ci-io aliphatic radical
• C 1-10 aliphatic radicals are each optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH 1 -SH and -NH 2 may be substituted;
• substituents independently of one another selected from the group consisting of oxo (OO), thioxo (SS), F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -OC 1-5 -alkyl, -NH 2 , -NO 2 , -O-
• heterocycloaliphatic radicals formed by R 11 and R 12 or R 13 and R 14 are each optionally 1, 2 or 3 additional heteroatom (s) independently selected from the group consisting of oxygen, nitrogen and sulfur Ring member (s) may have;
• radicals selected from the group consisting of phenyl, naphthyl (1,3) -benzodioxolyl, (1,4) -benzodioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, Indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, benzisoxazolyl, [1, 2 , 3,4] -t
• heteroaryl radicals may each optionally have 1, 2, 3, 4 or 5 heteroatom (s) independently selected from the group consisting of oxygen, nitrogen and sulfur as a ring member (s); in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
• heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur as a ring member (s); in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form of corresponding salts, or
• n 1;
• R 1 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, (1,1) -dimethyl-propyl, n-pentyl, sec Pentyl, n-hexyl and n-heptyl;
• a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
• R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 and R 8 independently of one another, respectively
• R 2 , R 4 , R 5 , R 6 , R 7 and R 8 independently of one another, respectively for a hydrogen radical
• R 1 , R 2 , R 7 and R 8 are each a hydrogen radical
• R 9 is a hydrogen radical
• cyclopropyl is a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and thiomorpholinyl, which has a - (CH 2 ) - or - (CH 2 ) 2 group may be bonded;
• R 13 is a radical selected from the group consisting of phenyl, naphthyl, (1,3) -benzodioxolyl, (1,4-benzodioxanyl, pyridinyl, quinazollinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzisoxazolyl and benzothiazolyl wherein the radical is optionally each with 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl 1 Br, I 1 -CN, -CF 3 , -SF 5 , -OH 1 - 0-CH 3 , -O-C 2 H 5 , -NH 2 , -NO 2 , -O-CF 3 , -S-CF 3 , -SH 1 -S-CH 3 , -SC 2 H 5 , methyl.
• R 12 and R 14 independently of one another, each represent a hydrogen radical
• pyridinyl, pyridazinyl, pyrimidinyl , [1,2,5] thiadiazolyl, thiazolyl, Phenyl and benzyl may be substituted, wherein in each case the cyclic part of the radicals pyrimidinyl, [1, 2,5] thiadiazolyl, thiazolyl, pyridinyl, pyridazinyl, phenyl and benzyl having 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -O-CH 3 , -O- C 2 H 5 , -O-CF 3 and -S-CF 3 may be substituted;
• R 15 , R 16 , R 19 and R 20 are each a hydrogen radical
• R 18 and R 22 are each independently a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and thiomorpholinyl stand,
• n 1,
• R 1 is a radical selected from the group consisting of methyl, ethyl, n-
• a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
• R 2 , R 7 and R 8 each represent a hydrogen radical
• R 1 and R 3 together represent a - (CH 2) 4 group
• R 2 , R 4 , R 7 and R 8 each represent a hydrogen radical
• R 1 , R 2 , R 7 and R 8 are each a hydrogen radical
• R 3 , R 4 , R 5 and R 6 independently of one another, each represent a methyl or ethyl radical
• R 9 is a hydrogen radical
• R 10 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, (1,1) -dimethyl-propyl, n-pentyl, sec Pentyl, n-hexyl and n-heptyl;
• phenyl is a radical selected from the group consisting of phenyl, indolyl, (1, 3) -benzodioxolyl, pyridinyl, (1, 4) -benzodioxanyl and naphthyl, the remainder being optionally in each case with 1, 2, 3, 4 or 5
• R 12 and R 14 independently of one another, each represent a hydrogen radical
• R 11 and R 12 or R 13 and R 14 each together with the nitrogen atom connecting them as a ring member
• n 1,
• R 1 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, (1,1) -dimethyl [-propyl, n-pentyl, sec-pentyl, n-hexyl and n-heptyl;
• a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
• R 2 , R 7 and R 8 each represent a hydrogen radical
• R 3 , R 4 , R 5 , R 6 independently of one another, respectively for a hydrogen radical or
• R 1 and R 3 together represent a - (CH 2 ) 4 group
• R 2 , R 4 , R 7 and R 8 each represent a hydrogen radical
• R 1 , R 2 , R 7 and R 8 are each a hydrogen radical
• R 3 , R 4 , R 5 and R 6 independently of one another, each represent a methyl or ethyl radical
• R 9 is a hydrogen radical
• R 10 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, (1,1) -dimethyl-propyl, n-pentyl, sec Pentyl, n-hexyl and n-heptyl;
• benzyl is a radical selected from the group consisting of benzyl, phenethyl, thiazolyl, naphthyl, (1, 3) -benzodioxolyl, (1, 4) -benzodioxanyl and pyridinyl, where the cyclic part of the abovementioned radicals optionally with 1, 2 , 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl 1 Br, I, -CF 3 , -OH 1 -O-CH 3 , -O-C 2 H 5 , methyl, ethyl, n- Propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl may be substituted;
• R 12 and R 14 independently of one another, each represent a hydrogen radical
• R 11 and R 12 or R 13 and R 14 each together with the nitrogen atom connecting them as a ring member
• substituted spiro compounds according to the invention may be preferred which, in the FLIPR assay at a concentration of 10 ⁇ M, inhibit the Ca 2+ ion influx in rat dorsal root ganglia of at least 10%, preferably at least 30%, more preferably at least 50%, most preferably of at least 70%, even more preferably of at least 90%, compared to the maximum achievable inhibition of Ca 2+ -ions inflow with capsaicin in a concentration of 10 uM have.
• Another object of the present invention is a process for the preparation of compounds of the invention of the above general formula I according to the at least one compound of general formula II,
• step 1 compounds of general formula II in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, tetrahydrofuran, dichloromethane and corresponding mixtures, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of Sodium bicarbonate, lithium hydroxide, triethylamine or N-diisopropylethylamine, reacted with compounds of general formula III at temperatures between 0 C C and 100 0 C to compounds of general formula IV.
• a reaction medium selected from the group consisting of methanol, tetrahydrofuran, dichloromethane and corresponding mixtures
• at least one base preferably in the presence of at least one base selected from the group consisting of Sodium bicarbonate, lithium hydroxide, triethylamine or N-diisopropylethylamine
• step 3 compounds of the above general formula V with amines of the general formula HNR 11 R 12 or compounds of the above formula VI with amines of the general formula HNR 13 R 14 in a reaction medium, preferably selected from the group consisting of diethyl ether, tetrahydrofuran , Acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N, N'-carbonyldiimidazole, N 1 N'-diisopropylcarbodiimide, N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI), N- [(Dimeth
• inorganic base preferably selected from the group consisting of potassium carbonate and cesium carbonate
• an organic base preferably selected from the group consisting of triethylamine, 4-methylmorpholine, pyridine, N, N-dimethylaminopyridine and diisopropylethylamine, preferably at temperatures from -70 0 C to 100 0 C to give
• the reactions described above may in each case be carried out under the customary conditions known to the person skilled in the art, for example with regard to pressure or sequence of addition of the components. Possibly. can be determined under the respective conditions optimal process control by the skilled person by simple preliminary tests.
• the intermediate and end products obtained according to the above-described reactions can each be purified and / or isolated, if desired and / or required, by customary methods known to those skilled in the art. Suitable purification methods are, for example, extraction methods and chromatographic methods, such as column chromatography or preparative chromatography. All of the above-mentioned process steps and in each case also the purification and / or isolation of intermediate or end products may be partially or completely under an inert gas atmosphere, preferably under Stickstoffatmosspreheat performed.
• substituted spiro compounds of the abovementioned general formulas I and Ia 1 according to the invention referred to below only as spiro compounds of the general formula I, and corresponding stereoisomers can be used both in the form of their free bases, their free acids and in the form of corresponding salts, in particular physiologically acceptable salts.
• the free bases of the particular substituted spiro compounds according to the invention of the abovementioned general formula I and corresponding stereoisomers can be synthesized, for example, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, Acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic or aspartic acid, in the corresponding salts, preferably physiologically acceptable salts, are transferred.
• an inorganic or organic acid preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, Acetic, oxalic, succinic, tartaric, mandelic, fumaric,
• the free bases of the respective substituted spiro compounds of the abovementioned general formula I and corresponding stereoisomers can likewise be converted into the corresponding physiologically tolerable salts with the free acid or a salt of a sugar substitute, such as, for example, saccharin, cyclamate or acesulfame. Accordingly, the free acids of the substituted spiro compounds of the abovementioned general formula I and corresponding stereoisomers can be converted into the corresponding physiologically tolerable salts by reaction with a suitable base.
• alkali metal salts alkaline earth metal salts or ammonium salts [NH x R 4 -X ] + , where x is 0, 1, 2, 3 or 4 and R is a linear or branched d 4 -alkyl radical, may be mentioned.
• substituted spiro compounds of the abovementioned general formula I and corresponding stereoisomers according to the invention may optionally, as well as the corresponding acids, the corresponding bases or salts of these compounds, according to conventional methods known in the art, also in the form of their solvates, preferably in the form of their Hydrate, to be obtained.
• substituted spiro compounds according to the invention of the abovementioned general formula I are obtained after their preparation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and / or diastereomers, these can be prepared by customary methods known to the person skilled in the art separated and possibly isolated.
• chromatographic separation processes in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MFlC and HPLC processes, as well as fractional crystallization processes.
• individual enantiomers for example by means of HPLC on a chiral stationary phase or by crystallization with chiral acids, such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10 camphorsulfonic acid, formed diastereomeric salts are separated.
• substituted spiro compounds according to the invention of the abovementioned general formula I and corresponding stereoisomers and in each case the corresponding acids, bases, salts and solvates are toxicologically harmless and are therefore suitable as pharmaceutical active ingredients in medicaments.
• Another object of the present invention is therefore a medicament containing at least one inventive spiro compound of the above general formula I, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients.
• medicaments according to the invention are particularly suitable for vanilloid receptor 1 (VR1 / TRPV1) regulation, preferably for vanilloid receptor 1 (VR1 / TRPV1) inhibition and / or for vanilloid receptor 1 (VR1 / TRPV1) stimulation.
• the medicaments according to the invention are likewise preferably suitable for the prophylaxis and / or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1.
• the medicament according to the invention is preferably suitable for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Joint pain; Migraine; Depressions; Neuropathy; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma and pneumonia; To cough; urinary incontinence; an overactive bladder (overactive bladder, OAB); Stomach ulcers; Irritable bowel syndrome; Stroke; Eye irritation; Skin irritation; neurotic skin diseases; Inflammatory diseases, preferably inflammations of the intestine; diarrhea; pruritus; Food ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug
• the medicament according to the invention is particularly preferably suitable for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; urinary incontinence; an overactive bladder (overactive bladder, OAB); Drug addiction; Drug abuse; Withdrawal symptoms in drug dependence; Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids; Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms in alcohol dependence.
• pain preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain
• Migraine Depressions
• neurodegenerative diseases preferably selected from the group consisting of multiple sclerosis,
• the pharmaceutical composition according to the invention is suitable for the treatment and / or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence.
• Another object of the present invention is the use of at least one substituted spiro compound according to the invention including the compounds excluded above and optionally one or more pharmaceutically acceptable excipients for the preparation of a medicament for vanilloid receptor 1- (VR1 / TRPV1) regulation, preferably Vanilloid Receptor 1 (VR1 / TRPV1) Inhibition and / or Vanilloid Receptor 1 (VR1 / TRPV1) Stimulation.
• VR1 / TRPV1 vanilloid receptor 1-
• V1 / TRPV1 Vanilloid Receptor 1
• V1 / TRPV1 Stimulation Vanilloid Receptor 1 Stimulation
• At least one substituted spiro compound according to the invention including the compounds excluded above and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Joint pain; Migraine; Depressions; Neuropathy; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; urinary incontinence; an overactive bladder (overactive bladder, OAB); Stomach ulcers; Irritable bowel syndrome; Stroke; diarrhea; pruritus; Food ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug addiction; Drug abuse; Withdrawal symptoms in drug dependence
• At least one substituted spiro compound according to the invention including the compounds excluded above and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of respiratory diseases, preferably selected from the group consisting of asthma and pneumonia; To cough; Eye irritation; Skin irritation; neurotic skin diseases; and inflammatory diseases, preferably inflammation of the intestine.
• At least one substituted spiro compound according to the invention including the compounds excluded above and optionally one or more pharmaceutically acceptable excipients for the preparation of a medicament for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; urinary incontinence; an overactive bladder (overactive bladder, OAB); Drug addiction; Drug abuse; Withdrawal symptoms in drug dependence; Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids; Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms in alcohol dependence.
• pain preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral
• At least one substituted spiro compound according to the invention including the compounds excluded above and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of pain, preferably selected from the group consisting of acute Pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence.
• the pharmaceutical composition of the invention is suitable for administration to adults and children, including infants and babies.
• the medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and as such also administered.
• the medicament of the invention usually contains further physiologically acceptable pharmaceutical excipients, which can be selected, for example, from the group consisting of support materials, fillers, solvents, Diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
• physiologically acceptable excipients depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, mucous membranes and on the eyes, to be applied.
• oral administration are preferably preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups, for parenteral, topical and inhalative administration solutions, suspensions, easily reconstitutable dry preparations and Sprays.
• substituted spiro compounds according to the invention which are used in the pharmaceutical composition according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can also release the respective substituted spiro compound according to the invention with a delay.
• the preparation of the pharmaceutical compositions according to the invention is carried out by means of conventional means, devices, methods and processes known from the prior art, as described, for example, in "Remington's Pharmaceutical Sciences", published by AR Gennaro, 17th edition, Mack Publishing Company, Easton, Pa , 1985, in particular in part 8, chapters 76 to 93.
• the corresponding description is hereby incorporated by reference and is part of the disclosure
• the amount of the respective substituted spiro compounds according to the invention of the above-indicated general formula I to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as the mode of administration, the indication and the severity of the disease. Usually 0.001 to 100 mg / kg, preferably 0.05 to 75 mg / kg, more preferably 0.05 to 50 mg / kg, body weight of the patient of at least one such V according to the invention compound applied.
• the agonistic or antagonistic action of the substances to be tested on the vanilloid receptor 1 (VR1 / TRPV1) of the rat species can be determined by the following assay.
• Ca 2+ influx through the receptor channel is monitored using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA ).
• FCS fetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany, heat-inactivated
• AA solution antioxidants / antimycotics solution, PAA, Pasching, Austria
• 25 ng / ml medium NGF 2.5S, Gibco Invitrogen GmbH, Düsseldorf, Germany
• Cell culture plate Poly-D-lysine-coated black 96-well plates with clear bottom (96 well black / clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany) by diluting laminin to a concentration of 100 ⁇ g / ml with PBS (Ca-Mg-free PBS, Gibco Invitrogen GmbH, Düsseldorf, Germany). Aliquots are taken at a concentration of 100 ug / mL of laminin and stored at -20 0 C.
• the aliquots are diluted with PBS in a ratio of 1:10 to 10 ⁇ g / ml laminin and pipetted in each case 50 .mu.l of the solution into a well of the cell culture plate.
• the cell culture plates are incubated for at least two hours at 37 ° C., and the supernatant is washed twice with PBS.
• the coated cell culture plates are stored with overhanging PBS and this is removed just before the task of the cells.
• Decapitated rats are removed from the vortex column and placed directly in cold, ie in an ice bath, HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) with 1% by volume (volume percent) of an AA solution (antibiotics / Antifungal solution, PAA, Pasching, Austria).
• HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
• AA solution antibiotics / Antifungal solution, PAA, Pasching, Austria
• the spinal column is severed longitudinally and taken together with fascia the vertebral canal. Subsequently, the dorsal root ganglia (DRGs) are removed and again stored in cold HBSS buffer mixed with 1% by volume of an AA solution.
• DDGs dorsal root ganglia
• the DRGs completely freed of blood residues and spinal nerves are each transferred into 500 ⁇ L of cold collagenase type 2 (PAA, Pasching, Austria) and incubated at 37 ° C. for 35 minutes. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria) is incubated at 37 0 C for a further 10 minutes. After the complete incubation, the enzyme solution is carefully pipetted off and the remaining DRGs are each mixed with 500 ⁇ l of complete medium.
• the DRGs are each resuspended several times, drawn through cannulae No. 1, No. 12 and No. 16 using a syringe and transferred to 50 mL Falcon tubes and this is made up to 15 mL with complete medium. The contents of each Falcon tube are each filtered through a 70 ⁇ m Falcon filter cartridge and centrifuged for 10 minutes at 1200 rpm at room temperature. The resulting pellet is taken up in 250 ⁇ L complete medium and the cell count is determined.
• the number of cells in the suspension is adjusted to 3 ⁇ 10 5 per mL and in each case 150 ⁇ L of this suspension are added to a well of the cell culture plates coated as described above. In the incubator, the plates at 37 0 C, 5 vol% CO 2 and 95% relative humidity allowed to stand for two to three days.
• the cells are incubated with 2 ⁇ M Fluo-4 and 0.01% by volume Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min 37 0 C, washed 3 times with HBSS buffer and after a further incubation for 15 minutes at room temperature for Ca 2+ measurement in FLIPR assay used.
• the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ M) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 10 ⁇ M). This gives the indication in% activation based on the Ca 2+ signal after addition of 10 ⁇ M capsaicin (CP). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined.
• the agonistic or antagonistic effect of the substances to be examined on vanilloid receptor (VR1) can also be determined by the following assay.
• Ca 2+ influx through the channel is monitored using a Ca 2+ -sensitive dye (Fluo-4, Molecular Probes, Europe BV, Leiden, The Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale , USA).
• FLIPR Fluorescent Imaging Plate Reader
• CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) Great Britain) are stably transfected with the VR1 gene. For functional studies, these cells are plated on poly-D-lysine-coated black 96-well clear bottom plates (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells / well. Overnight, the cells are incubated at 37 ° C. and 5% CO 2 in a culture medium (Nutrient Mixture Ham's F12, 10% by volume FCS (Fetal calf serum), 18 ⁇ g / ml L-proline).
• a culture medium Nutrient Mixture Ham's F12, 10% by volume FCS (Fetal calf serum), 18 ⁇ g / ml L-proline.
• Fluo-4 Fluo-42 ⁇ M, Pluronic F1270.01% by volume, Molecular Probes in HBSS (Hanks buffered saline solution), Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 minutes at 37
• the FLIPR protocol consists of 2 substance additions. At first, the substances to be tested (10 .mu.M) are pipetted onto the cells and the Ca 2+ influx with the control (capsaicin 10 .mu.M) compared (% activation based on the Ca 2+ 'signal after addition of 10 uM capsaicin). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined.
• the first (early) phase (0 to 15 minutes after formalin injection) and the second (late) phase (15 to 60 minutes after formalin injection).
• the early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain (T J. Coderre et al., Pain 1993, 52, 259-285).
• the corresponding literature descriptions are hereby incorporated by reference and are considered part of the disclosure.
• the compounds according to the invention are investigated in the second phase of the Formarm test in order to obtain statements about substance effects on chronic / inflammatory pain.
• the time of application of the compounds according to the invention prior to the formalin injection is selected.
• the intravenous administration of 10 mg / kg body weight of the test substances takes place 5 minutes before the formalin injection. This is done by a single subcutaneous injection of formalin (20 .mu.L, 1% aqueous solution) in the dorsal side of the right hindpaw, so that in nociceptive experimental animals a nociceptive reaction is induced, which manifests itself in significant licking and biting of the paw in question ,
• nociceptive behavior is continuously monitored by observation of the animals.
• the pain behavior is quantified by the summation of the seconds in which the animals show a licking and biting of the affected paw during the examination period.
• the comparison is carried out in each case with control animals, which receive instead of the compounds of the invention vehicle (0.9% aqueous sodium chloride solution) before formalin. Based on the quantification of pain behavior, the substance effect in the formalin test is determined as a change from the corresponding control in percent.
• mice Male NMRI mice weighing 25 to 30 g were used. Groups of 10 animals per compound dose were given 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, Germany, 10 minutes after intravenous administration of the compounds to be investigated; Wt .-% ethanol and storage in a water bath at 45 ° C) intraperitoneally applied. The animals were placed individually in observation cages. By means of a push-button counter, the number of pain-induced stretching movements (so-called writhing reactions) was counted 5 to 20 minutes after the phenylquinone administration.
• phenylquinone phenylbenzoquinone
• the chemicals and solvents used were obtained commercially from the conventional suppliers (Acros, Avocado, Aldrich, Bachern, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized according to methods known to those skilled in the art.
• Methyltriphenylphosphonium bromide (17.4 g, 48.6 mmol) was dissolved in abs. Diethyl ether (106 ml) under nitrogen atmosphere. At 0 0 C potassium tert-butoxide (5.0 g, 45.4 mmol) was added thereto slowly. After 30 minutes, again at 0 0 C 4-tert-butylcyclohexanone (5.0 g, 32.4 mmol) slowly as a solution in diethyl ether (10 rril) was added dropwise. The reaction mixture was stirred at RT overnight. For workup, the reaction mixture was cooled in an ice bath and washed with sat. aq. NHUCI solution.
• ester 8- (1,1-dimethylpropyl) -1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid ethyl ester was obtained as a colorless solid in a yield of 36% (3.0 g) with a melting point isolated from 82-87 0 C.
• ester 8- (1,1-dimethylpropyl) -1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid ethyl ester (2.8 g, 10 mmol) was dissolved in MeOH (50 ml), washed with Lithium hydroxide (357 mg, 15 mmol) in water (8 ml) and stirred for 23 h at RT. To work up the reaction, MeOH was removed in vacuo and water (25 ml) added. After the addition of 10% aq. Citric acid sol.
• ester 8-cyclohexyl-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid ethyl ester (2.5g, 8.5mmol) was dissolved in MeOH (80ml) with heating, with lithium hydroxide (306mg , 13 mmol) in water (8 ml) and stirred at RT for 60 h. To work up the reaction, MeOH was removed in vacuo and water (25 ml) added. After the addition of 10% aq. Citric acid sol. (20 ml) precipitated at pH 4 the acid 8-cyclohexyl-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid.
• the light pink residue was the mixture of diastereoisomers of 8-tert-butyl-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid (3-fluoro-4-methanesulfonylaminophenyl) amide (353 mg, m.p. 104-107 0 C and 228-232 0 C, 55%).
• the product mixture was purified by flash chromatography [Kieselgel 60 (30 g); Eluent: cyclohexane / EtOAc (4: 1, 500 mL), cyclohexane / EtOAc (3: 1, 400 mL), and cyclohexane / EtOAc (1: 1; 300 mL)].
• the mixture of the diastereoisomers 8-fer-butyl-i-oxa-azaspiro-.delta-decene-5-S-carboxylic acid p-fluoro (bismethanesulfonyl) aminophenyl] amide (89 mg, mp.
• the viscous residue was dissolved in 0.5 N aq. HCl (10 ml) and EtOAc (10 ml). The phases were separated. The organic phase was washed successively with 0.5 N aq. HCl (2 * 5 ml), with 1.1 M aq. NaHCO 3 (3 ⁇ 5 ml) and water (2 * 5 ml). The organic phase was dried with NaaSO 4 . The solvent was distilled off. The beige residue was the mixture of diastereoisomers of 8-th /?
• the reaction mixture was dark brown in color and contained little precipitate.
• THF was distilled off.
• the residue was dissolved in 0.5 N aq. HCl (7 ml), water (5 ml) and EtOAc (35 ml).
• the phases were separated.
• the organic phase was washed successively with 0.5 N aq. HCl (2 x 7 mL), 1.1 M aq. NaHCO 3 sol. (3 x 10 ml) and water (2 x 5 ml).
• the organic phase was dried with Na 2 SO 4 .
• the solvent was distilled off.
• Citric acid sol. (20 ml) stirred for 10 min. Then the phases were separated and the organic phase was washed with sat. aq. NaHCO 3 solution (2 x 15 ml) and with sat. aq. NaCl solution (1 x 15 ml). The organic phase was dried and concentrated. The residue was purified by column chromatography [silica gel 60 (70 g); Cyclohexane / EtOAc (5: 1, 500 ml); EtOAc (500 ml)].
• Methyltriphenylphosphonium bromide (34.1 g, 95.5 mmol) was dissolved in abs. Diethyl ether (420 ml) submitted under nitrogen atmosphere. Potassium tert-butylate (13.1 g, 113.1 mmol) was added slowly at O C C. After 30 min, ethyM-oxocyclohexanecarboxylate (10.7 g, 62.9 mmol) as a solution in diethyl ether (80 ml) was again slowly added dropwise at 0 ° C. The reaction mixture was stirred at RT overnight. For workup, the reaction mixture was cooled in an ice bath and washed with sat. aq. NH 4 Cl solution.
• the reaction mixture was diluted with DCM and with water.
• the combined organic phases were 10%. aq. citric acid solution. and ges. Washed aq. NaCl solution, dried over sodium sulfate and the solvent removed in vacuo.
• the desired product 3-phenyl-1-oxa-2-aza-spiro [4.5] dec-2-ene-8-carboxylic acid ethyl ester as a white solid (190 mg, 25% of theory).
• N-ethyldiisopropylamine 662 g, 4.6 mmol
• 1-hydroxybenzotriazole hydrate 206 mg, 1.54 mmol
• O- (benzotriazole-1-VI) -N 1 N 1 N ', N'-tetramethyluronium tetrafluoroborate 496 mg , 1.54 mmol
• N- (4-aminomethyl-2-fluorophenyl) -methanesulfonamide (336 mg, 1.54 mmol) in abs.
• the organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO 3 sol., sat. aq. ammonium sulfate solution. and ges. aq. NaCl solution. washed, dried over magnesium sulfate and the solvent removed in vacuo. The residue was in EtOAc (2.5 ml) and DCM (1 ml) boiled. The resulting precipitate was filtered off with suction and washed with a little ether.
• Methyltriphenylphosphonium bromide (89.2 g, 249 mmol) was dissolved in abs. Diethyl ether (800 ml) submitted under nitrogen atmosphere. At 0 0 C was slowly added potassium tert-butoxide (34 g, 295 mmol) was added. After 30 min, octahydro-naphthalen-2-one (25 g, 164 mmol) was again slowly added dropwise at 0 ° C. as a solution in diethyl ether (500 ml). The reaction mixture was stirred at RT overnight. For workup, the reaction mixture was cooled in an ice bath and washed with sat. aq. NH 4 Cl-LSg. added.

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